Mapping Interactive Cancer Susceptibility Genes in Prostate Cancer

We have employed a large prostate cancer affected sibling pair cohort for candidate gene based linkage analyses. In this work we sought to enlarge a pre-existing cohort of CaP Prostate Cancer ASP with continued institutional recruitment of brothers affected with disease. We performed candidate gene based fine structure linkage analysis on approximately 2 dozen genes previously implicated in CaP risk. We also tested gene x gene interactions with a new paradigm based upon allele sharing enrichment. Our major finding was the localization of a susceptibility locus to intron 5 of the FHIT gene. By utilizing a combination of extensive mutationsingle nucleotide polymorphism SNP discovery efforts in select disease cases in conjunction with linkage disequilibrium LD mapping and association testing we identified a SNP, rs760317, showing strong association with disease in affected brothers sharing 2 alleles identify by descent IBD. The findings were published in 2005 and have recently been replicated by independent researchers in both a family-based Caucasian patient cohort and an African American patient cohort. Our efforts represent a significant accomplishment in the identification of a new gene associated with CaP risk as quite often promising initial linkage or association results fail to be replicated in independent studies. We continue our efforts today with the hope of finding the causative alleles in FHIT and ittheir possible function using population genetic tools. This represents extreme challenges as the mechanistic basis for how disease alleles residing deep within the introns contribute to disease risk.